Harold Fisk

Focus

Centrosome duplication, cell cycle regulation, mitotic spindle assembly, protein kinase.

Research interests

See the Fisk lab website at:

http://www.biosci.ohio-state.edu/~hafisk

My laboratory is interested in understanding how the centrosome organelle is assembled, and how defects in this process might lead to the chromosome segregation errors associated with human cancer cells. Centrosomes are microtubule-organizing centers that act as poles of the mitotic spindle apparatus to regulate its assembly and function. Centrosomes make additional contributions to chromosome segregation by regulating cytokinesis and the decision to enter the subsequent cell cycle. It is therefore easy to imagine how defects in centrosome function might cause chromosome segregation errors. Because centrosomes make many contributions to the fidelity of chromosome segregation, and because most human tumors are aneuploid as a result of errors in chromosome segregation, it is not surprising that defects in the number, structure, and function of centrosomes are associated with many human tumors.

Like the genome, centrosomes are single copy organelles that must be precisely duplicated prior to cell division. RNA interference techniques have shown that the Mps1 protein kinase (which is found at centrosomes) is required for centrosome duplication in human cells. Furthermore, overexpression of Mps1 in mouse cells causes multiple rounds of centrosome duplication, leading to the production of abnormal mitotic spindles. Mps1 is normally an unstable protein, and biochemical studies have shown that its function in centrosome duplication is controlled by proteasome-mediated degradation. However, Mps1 is aberrantly stable in many human tumor-derived cells, and RT-PCR analysis has identified a mutant form of Mps1 from one such cell line. This mutant form of Mps1 cannot be properly degraded, and deregulates centrosome duplication in a variety of human cell types.

The goal of my research program is to understand the mechanisms of centrosome duplication in human cells, and to determine how this process is regulated and integrated into the cell cycle. The primary focus of my lab will be on the precise function of Mps1, its regulation, and its relevance to cancer. We will use a combination of cell biological, biochemical, and molecular biological techniques to investigate the function of Mps1, identify the substrates of Mps1 kinase activity, and characterize relationships between Mps1 and other centrosomal proteins. One major effort in the lab is to develop a cell-based assay to biochemically reconstitute centrosome duplication, with the ultimate goal of defining the molecular pathway for this critical process. My lab will also investigate two additional functions of Mps1, in the spindle checkpoint, and in cytokinesis. Finally, we will explore the relationships between Mps1 stability, centrosome duplication, and tumorigenesis by characterizing additional instances of Mps1 misregulation in human tumor-derived cells, and by utilizing the mouse as an experimental model to explore the biological consequences of aberrant Mps1 stabilization.

 

Dr. Fisk has a joint appointment in the Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, OSU College of Medicine.

Additional Information at the HCG website: http://cancergenetics.med.ohio-state.edu/3237.cfm

 

Publications

• Kasbek, C. C.-H. Yang, A. Mohd Yusof, H. M. Chapman, M. Winey, and H. A. Fisk, Preventing the degradation of Mps1 at centrosomes is sufficient to cause centrosome re-duplication in human cells. Mol Biol Cell (2007) 18:4457-69.
• Fisk, H.A. and M. Winey, Spindle Regulation: Mps1 flies into new areas. Current Biology (2004) 14:R1058-60.
• Fisk, H.A., C.P. Mattison, and M. Winey, A field guide to the Mps1 family of protein kinases. Cell Cycle (2004) 3:439-442.
• Fisk, H.A., C.P. Mattison, and M. Winey, Human Mps1 protein kinase is required for centrosome duplication and normal mitotic progression. Proc Natl Acad Sci U S A (2003) 100:14875-80.
• Fisk, H.A., C.P. Mattison, and M. Winey, Centrosomes and tumour suppressors. Curr Opin Cell Biol (2002) 14:700-5.
• Fisk, H.A. and M. Winey, The mouse mps1p-like kinase regulates centrosome duplication. Cell (2001) 106:95-104.